15-Epi-prostacyclin and analogous prostacyclins

ABSTRACT

15-Epi-Prostacyclin derivatives and compositions containing them having numerous pharmaceutical and veterinary utilities including, for example, anti-aggregating activity and anti-thrombolytic activity. Methods for preparing and using the compounds are also disclosed.

This is a Divisional application of Ser. No. 955,631, filed Oct. 30,1978 now U.S. Pat. No. 4,285,966 8-25-81.

The present invention relates to 15-epi-derivatives of9-deoxy-6,9α-epoxy-Δ⁵ -PGF₁α (prostacyclin or PGI₂) and analogousprostacyclins, to a process for their preparation and to pharmaceuticaland veterinary compositions containing them.

The compounds covered by this invention are bicyclic prostaglandins offormula (I) ##STR1## wherein R is a substituent chosen from thefollowing: (a) --COOR' wherein R' is hydrogen or C₁ -C₆ alkyl; (b) --CH₂OH; (c) ##STR2## in which the R" groups, whether the same or different,are C₁ -C₆ alkyl or phenyl; (d) ##STR3## in which R_(a) and R_(b) areindependently chosen from hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkanoyl andphenyl; (e) ##STR4## radical; (f) --C.tbd.N; p is zero or an integerbetween 1 and 7;

q is 1 or 2;

R₁ is hydrogen, hydroxy, C₁ -C₆ alkoxy, aryl-C₁ -C₆ -alkoxy, acyloxy;

Y is chosen from the group: --CH₂ --CH₂ --, --C.tbd.C--, ##STR5## (cis),##STR6## (trans) where Z₁ is hydrogen or halogen; R₂ is hydrogen, C₁ -C₆alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ alkynyl, aryl;

R₅ is hydrogen, C₁ -C₆ alkyl, aryl-C₁ -C₆ -alkyl;

n₁ and n₂, whether the same or different, are zero or an integer between1 and 6;

R₃ and R₄, whether the same or different, may be hydrogen, C₁ -C₆ alkylor fluorine, or may form a ##STR7## group with a carbon atom to whichthey are bound; X is chosen from --O--, --S-- and --(CH₂)_(m) wherein mis zero or 1;

R₆ is a substituent chosen from (a') hydrogen, (b') C₁ -C₄ alkyl; (c') acycloaliphatic radical, optionally substituted with one or more C₁ -C₆alkyl and C₁ -C₆ alkoxy groups; (d') an aryl group optionallysubstituted with one or more halogen, C₁ -C₆ alkyl, halo-C₁ -C₆ -alkylor C₁ -C₆ -alkoxy; (e') a saturated or unsaturated heterocyclic radicaloptionally substituted with one or more halogen, C₁ -C₆ alkyl, C₁ -C₆alkoxy, or halo-C₁ -C₆ -alkyl.

This invention also includes pharmaceutically and veterinarilyacceptable salts of compounds with formula (I), as well as the opticalantipodes (the enantiomers), racemic mixtures of the optical antipodes,geometric isomers and their mixtures, and mixtures of diastereomers.

In this discussion, dashed lines (||||) refer to a substituent on a ringin the α(or endo) configuration or to a substituent in the Sconfiguration on a chain. On the other hand, a wedge ( ) indicates thata ring substituent is β(or exo) or that a chain substituent is R. A wavyline ( ) implies that the substituent may be in both the α(endo) orβ(exo) configuration if on a ring, or in the S or R form if on a chain.

In formula (I), the two bonds in the heterocyclic ring B drawn withdashed lines (|||||) are cis to one another, while the side chain boundto the cyclopentane ring A is trans to heterocyclic ring B.

Compounds of the invention are both the isomers of formula (I) whereinthe double bond exocyclic to heterocycle B is in Z (cis) or in E (trans)configuration and the mixtures of said isomers. In the natural series'compounds (nat-derivatives), this exocyclic double bond preferably is Z;while in the corresponding enantio derivatives (ent-derivatives),preferably it is E.

The alkyl, alkenyl, alkynyl, alkoxy and alkanoyl groups may be straightor branched chains.

R is preferably a --COOH group.

The C₁ -C₆ alkyl group is preferably methyl, ethyl or propyl.

The C₂ -C₆ alkanoyl is preferably acetyl or propionyl.

The C₁ -C₆ alkoxy is preferably methoxy, ethoxy or propoxy.

The C₂ -C₆ alkenyl is preferably vinyl, allyl or propenyl.

The C₂ -C₆ alkynyl is preferably ethynyl.

The aryl group is preferably phenyl, tolyl, α-naphthyl or β-naphthyl.

A phenyl group may be unsubstituted or substituted with one or moresubstituents chosen from C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halo-C₁ -C₆ alkyland halogen.

An aryl-C₁ -C₆ -alkyl group is preferably benzyl and an aryl-C₁ -C₆-alkoxy is preferably benzyloxy.

A halo-C₁ -C₆ -alkyl is preferably trihalo-C₁ -C₆ -alkyl, particularlytrifluoromethyl and trichloromethyl.

An acyloxy group is preferably alkanoyl-oxy, particularly acetoxy orpropionyloxy, or benzoyloxy.

When Z₁ is halogen, chlorine, bromine or iodine is preferred.

Preferably, R₃ and R₄ are independently chosen from hydrogen, C₁ -C₆-alkyl and fluorine.

n₁ is preferably zero or an integer between 1 and 3; n₂ is preferably aninteger between 1 and 3.

When R₆ is C₁ -C₄ alkyl, methyl is preferred. When R₆ is acycloaliphatic radical, it may be mono-, bi- or tri-cyclic. Ifmonocyclic, a C₃ -C₉ cycloalkyl or cycloalkenyl is preferred,particularly cyclopentyl, cyclohexenyl, cycloheptyl, cyclopentenyl orcycloheptenyl. When R₆ is bicyclic or tricyclic, norbornyl or adamantylgroups are preferred, respectively.

If R₆ is a cycloaliphatic group, it is preferably a monocycliccycloalkyl, like cyclohexyl.

When R₆ is a heterocyclic radical, this may be mono- or bi-cyclic andcontains at least one heteroatom chosen from the group O, S, N. Examplesof preferred heteromonocyclic radicals include tetrahydrofuryl, furyl,tetrahydrothienyl, thienyl, tetrahydropyranyl, pyrrolyl, pyrazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrinidinyl, pyridazinyl.Preferred heterocicyclic radicals include 2-oxa and2-thio-bicyclo[3.3.0]octyl, 2-oxa- and 2-thio-bicyclo[3.4.0]nonyl, aswell as their aromatic analogues.

Pharmaceutically or veterinarily acceptable salts of compounds (I) arepreferably formed with both inorganic and organic bases.

As examples, acceptable inorganic bases are alkali, e.g. sodium orpotassium; alkaline earth, e.g. calcium, zinc or aluminium hydroxides.Acceptable organic bases include organic amines like methylamine,diethylamine, trimethylamine, triethylamine, ethylamine, dibutylamine,triisopropylamine, N-methyl-hexylamine, decylamine, dodecylamine,allylamine, crotylamine, dicyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, as well as similar aliphaticcycloaliphatic, aromatic or heterocyclic amines like piperidine,morpholine, pyrrolidine, piperazine. Substituted derivatives of thelatter like 1-methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine or amines containing hydrophilic groups like mono-,di- and tri-ethanol amine, 2-amino-1-butanol,2-amino-2-ethyl-1,3-butyl-ethanolamine, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris-(hydroxymethyl)-aminomethane,N-phenyl-ethanolamine, N-(p-tert-amylphenyl)-diethanolamine, ephedrine,procain may also be acceptably used.

According to this invention, preferred salts of compound (I) are thosein which R is a --COOR_(d) group where R_(d) is a pharmaceutically orveterinarily acceptable cation derived from one of the bases mentionedabove. Preferred compounds of the invention are the compounds of formula(I) wherein R is --COOR', wherein R' is as defined above or ##STR8##wherein R_(a) and R_(b) are as defined above; Y is cis or trans--CH═CH-- or --C.tbd.C--; p, q, R₁, R₂, R₅, n₁, n₂, R₃, R₄, X and R₆ areas defined above, as well as the pharmaceutical or veterinary acceptablesalts thereof. Particularly preferred compounds of the invention are thecompounds of formula (I) wherein R is --COOR', wherein R' is hydrogen orC₁ -C₆ alkyl; p is an integer of 1 to 5; q is 1 or 2; Y is trans-CH═CH--or --C.tbd.C--; R₁ is hydrogen or hydroxy; R₂ is hydrogen or C₁ -C₆alkyl; R₅ is hydrogen or C₁ -C₆ alkyl; n₁ and n₂ are, independently,zero or an integer of 1 to 3; R₃ and R₄ are, independently, hydrogen, C₁-C.sub. 6 alkyl or fluorine; X is --O-- or --(CH₂)_(m) -- wherein m iszero or 1; R₆ is a substituent chosen from (a') hydrogen; (b') C₁ -C₄alkyl; (c') a monocyclic C₃ -C₉ cycloaliphatic radical optionallysubstituted with one or more C₁ -C₆ alkyl and C₁ -C₆ alkoxy groups; (d')a phenyl group optionally substituted with one or more halogen,trihalo-C₁ -C₆ -alkyl, C₁ -C₆ alkyl and C₁ -C₆ alkoxy, as well as thepharmaceutical or veterinary acceptable salts thereof. More particularlypreferred compounds of the invention are the compounds of formula (I)wherein R is --COOR', wherein R' is hydrogen or C₁ -C₆ alkyl; p is 3; qis 1; R₁ is hydrogen or hydroxy; Y is trans-CH═CH-- or --C.tbd.C--,preferably --C.tbd.C--; R₂ is hydrogen or C₁ -C₆ alkyl; R₅ is hydrogenor C₁ -C₆ alkyl; n₁ is zero or 1; R₃ and R₄ are, independently,hydrogen, methyl or fluorine; X is --O-- or --(CH₂)_(m) -- wherein m iszero or 1; n₂ is zero or an integer of 1 to 3; R₆ is hydrogen or C₁ -C₄alkyl, as well as the pharmaceutical or veterinary acceptable saltsthereof. Examples of compounds preferred under this invention are:

d,1-15-epi-PGI₂ ;

nat-15-epi-PGI₂ ;

ent-15-epi-PGI₂ ;

nat-11,15-diepi-PGI₂ ;

ent-11,15-diepi-PGI₂ ;

and the compounds listed below both in the d,l forms and as individualnat- and enantio-isomers;

15-epi-13,14-dehydro-PGI₂ ;

15-eip-20-methyl-PGI₂ ;

15-epi-20-methyl-13,14-dehydro-PGI₂ ;

15-epi-16S,20-dimethyl-PGI₂ ;

15-epi-16R,20-dimethyl-PGI₂ ;

15-epi-20-ethyl-PGI₂ ;

15-epi-16S-methyl-PGI₂ ;

15-epi-16S-methyl-13,14-dehydro-PGI₂ ;

15-eip-16R-methyl-PGI₂ ;

15-epi-16,16-dimethyl-PGI₂ ;

15-epi-17-oxa-PGI₂ ;

15-epi-17-oxa-20-methyl-PGI₂ ;

15-epi-17-trinor-17-(2'-tetrahydrofuryl)-PGI₂ ;

15-epi-17-trinor-17-(2'-furyl)-PGI₂ ;

15-epi-17-trinor-17-phenyl-PGI₂ ;

15-epi-17-trinor-17-cyclohexyl-PGI₂ ;

15-epi-17-trinor-17-cyclopentyl-PGI₂ ;

15-epi-16-tetranor-16-phenoxy-PGI₂ ;

15-epi-16-tetranor-16-m-trifluoromethylphenoxy-PGI₂ ;

15-epi-16-tetranor-16-p-fluorophenoxy-PGI₂ ;

15-epi-16-tetranor-16-phenyl-PGI₂ ;

15-epi-16-tetranor-16-cyclohexyl-PGI₂ ;

15-epi-16-tetranor-16-(2'-norbornyl)-PGI₂ ;

15-epi-13,14-dihydro-PGI₂ ;

15-epi-13,14-dehydro-16(R) or (S,R)-methyl-PGI₂ ;

15-epi-16(S),(R) or (S,R)-fluoro-PGI₂ ;

15-epi-17-trinor-16-methyl-16-butoxy-PGI₂ ;

15-epi-17-trinor-16-methyl-16-propoxy-PGI₂ ;

15-epi-17-trinor-16-methyl-16-amyloxy-PGI₂ ;

15-epi-17-trinor-16(S),(R) or (S,R)-fluoro-17-cyclohexyl-PGI₂ ;

15-epi-17-trinor-13,14-dehydro-17-cyclohexyl-PGI₂ ;

15-epi-17-trinor-13,14-dehydro-17-phenyl-PGI₂ ;

15-epi-17-trinor-13,14-dehydro-16(S),(R) or(S,R)-fluoro-17-cyclohexyl-PGI₂ ;

15-epi-16-tetranor-16-m-chlorophenoxy-PGI₂ ;

15-epi-16-tetranor-16-p-chlorophenoxy-PGI₂ ;

15-epi-16-tetranor-16-butoxy-PGI₂ ;

15-epi-11-deoxy-PGI₂ ;

15-epi-11-deoxy-16S-methyl-13,14-dehydro-PGI₂ ;

15-epi-11-deoxy-16S-methyl-PGI₂ ;

15-epi-11-deoxy-16,16-dimethyl-17-oxa-PGI₂ ;

15-epi-11-deoxy-16,16,20-trimethyl-17-oxa-PGI₂ ;

15-epi-11-deoxy-16,16-dimethyl-20-ethyl-17-oxa-PGI₂ ;

and the corresponding 11,15-diepi derivatives as well as thepharmaceutical or veterinary acceptable salts of all the compoundslisted above.

Belgian Pat. No. 851,122 (Derwent-Farmdoc number 57511 Y) describes9-oxide-6,9α-epoxy-Δ⁵ -PGF₁α. In addition to other effects, it inhibitsplatelet aggregation and prevents thrombus formation while acting as ahypotensive vasodilatory.

This Belgian patent also reports that the best biological response interms of the specificity, potency and duration of effect is seen withthe 15S-hydroxy-9-oxide-6,9α-epoxy-Δ⁵ -PGF₁α derivatives, which arealmost the only compounds described in the patent. This is consistentwith several literature reports that 15-epi or 15R-hydroxy derivativesare generally less active than the corresponding 15S-hydroxy epimers.

In addition to not being specifically mentioned in the Belgian patentcited above, the 15-epi derivatives in this invention are important fortheir prostacyclin -like activity: in particular, the ability to inhibitplatelet aggregation, to dissolve clots, to cause the coronary vesselsto dilate, all with no undesirable side effects. However, for thenatural prostacyclins (the 15S-derivatives), for example the compoundsdescribed in the above mentioned Belgian patent, this activity is alwaysassociated with a general vaso-dilatory effect which causes hypotension.It must be noted that the Belgian patent attributes no thrombolyticactivity to the compounds it covers. However, the 15-epi-prostacyclinderivatives described by the present invention do not produce generalvaso-dilatation and so have no hypotensive effect.

Due to this particular characteristic, the compounds covered by thisinvention are excellent anti-thrombotic and thrombolytic agents usefulin the treatment of acute myocardial infarction.

A compound used to treat myocardial infarction must be absolutely freeof negative effects on systemic pressure: there must be no vaso-dilatoryand hypotensive effect. This undesirable side effect is characteristicof natural prostacyclins like the 15S-derivatives described in BelgianPat. No. 851,122 but is not seen for the compounds covered by thepresent invention. In addition to dissolving thrombi and clots, theseare selective vaso-dilators at the coronary level with no generalhypotensive effect nor undesirable side effects like the stimulation ofthe gastro-intestinal tract.

In this regard, a comparison of 15-epi-d,l-PGI₂ with the analogous15S-d,l-PGI₂, and of these compounds with PGI₂, PGE₁, 5,6α-dihydro-PGI₂and ω-tetranor-16-m-CF₃ -phenoxy-5,6α-dihydro-PGI₂ is of interest. Thefollowing graph shows their inhibition of platelet aggregation (percent)induced by 2 μM ADP in platelet rich plasma: ##STR9## Expressed as IC₅₀ng/ml (50% platelets aggregation inhibiting concentration) theirapproximate activities are:

    ______________________________________                                        PGI.sub.2 * and d,l-PGI.sub.2                                                                           ≅4.5                                      PGE.sub.1                 ≅30                                       d,l-15-epi-PGE.sub.2      ≅330                                      5,6α-dihydro-PGI.sub.2                                                                            ≅400                                      ω-tetranor-16-m-CF.sub.3 -phenoxy-5,6α-dihydro-PGI.sub.2                                    >5000                                               d,l-5,6α-dihydro-15-epi-PGI.sub.2                                                                 not active                                          d,l-5,6β-dihydro-15-epi-PGI.sub.2                                                                  not active                                          ______________________________________                                    

Another important characteristic of these new 15-epi prostacyclineanalogues is that they show practically no PGE-like activity in thegastro-intestinal tract. Unlike the analogous15S-hydroxy-5,6α-dihydro-prostacyclins and their 15-epi derivatives(totally inactive in the preceding test), these new compounds induce nocontractions in the rat colon or in stomachs strips.

With PGE₂ as standard (100), potency ratios are as follows:

    ______________________________________                                                           rat     stomach                                                               colon   strips                                             ______________________________________                                        PGE.sub.2            100       100                                            PGI.sub.2 *          0         20                                             d,l-PGI.sub.2        0         20                                             15-epi-d,l-PGI.sub.2 0         1                                              5,6α-dihydro-PGI.sub.2                                                                       2.76      1.86                                           5,6β-dihydro-PGI.sub.2                                                                        2         0.80                                           16,16-dimethyl-17-oxa-5,6α-                                             dihydro-PGI.sub.2    0.72      0.41**                                         ω-tetranor-16-m-CF.sub.3 -phenoxy-                                      5,6α-dihydro-PGI.sub.2                                                                       2.8       0.91                                           d,l-5,6α-dihdyro-15-epi-PGI.sub.2                                                            0         0.20                                           d,l-5,6β-dihydro-15-epi-PGI.sub.2                                                             0         0.05                                           ______________________________________                                         **This compound shows weak platelet aggregant activity.                  

Of further importance is the effect of these 15-epi derivatives as arelaxant and dilatory for bovine coronary arteries. Once again, theycompare favorably with the 5,6-dihydro-PGI₂ analogues (that is, with the15S-hydroxy):

    ______________________________________                                                         Dilation,                                                                     bovine Contraction,                                                           coronary                                                                             bovine coronary                                                        artery artery                                                ______________________________________                                        PGI.sub.2 *        100      0                                                 d,l-PGI.sub.2      100      0                                                 d,l-15-epi-PGI.sub.2                                                                             1        0                                                 5,6α-dihydro-PGI.sub.2                                                                     0.28     0                                                 5,6β-dihydro-PGI.sub.2                                                                      0        0.34                                              15-epi-d,l-5,6α-dihydro-PGI.sub.2                                                          0        0                                                 15-epi-d,l-5,6β-dihydro-PGI.sub.2                                                           0        0                                                 ω-tetranor-16-m-CF.sub.3 -phenoxy-5,6α-                           dihydro-PGI.sub.2  0.11     0                                                 PGE.sub.2          0        100                                               ______________________________________                                    

In all of these areas (platelet aggregation inhibition, coronary vesseldilation, absence or attenuation of undesirable side effects), the rangeof activity does not differ substantially from that of the naturalproduct PGI₂, compared to which there is a foreseeable (for a 15-epiderivative) decrease in potency. Therefore, these new compounds are notof necessity preferred to the natural product, to the 5,6-dihydroanalogues, e.g. 5,6α-dihydro-PGI₂, or to the tetranor derivative whichis less active than the natural product, but more stable.

However, the innovative and new aspect of these new 15-epi compounds isrevealed by testing then using Gryglewsky's technique (Abstract II Int.Symp. on Prostaglandins, Halle, Sept. 19-21, 1977, pag. 3) onanesthetized and herparinized cats to determine their clot disaggregantcapacity in vivo. In this test, a PGI₂ dose of 2.5 μg/kg i.v. blocks theplatelet aggregation phenomenon; the 5,6α-dihydro-PGI₂ (a 15S-hydroxyderivative) dose showing equal activity is 250 μg/kg i.v. So, forequally active disaggregant doses, the hypotensive effect isapproximately 25% higher than that of PGI₂. The ω-tetranor analogue is15 times less active as an anti-aggregant, while d,l-15-epi-PGI₂requires 125 μg/kg i.v. to give the same effect as the above dose ofPGI₂. Therefore the following scale of equi-active doses results:

    ______________________________________                                        PGI.sub.2             2.5 μg/kg                                            d,l-PGI.sub.2         4-5 μg/kg                                            d,l-15-epi-PGI.sub.2  125 μg/kg                                            5,6α-dihyro-PGI.sub.2                                                                         250 μg/kg                                            ______________________________________                                    

However, in terms of the present invention it is important and relevantthat unlike biosynthetic-origin PGI₂ (from arachidonic acid), d,l-PGI₂and 5,6α-dihydro-PGI₂ (which are all prostacyclin-like compounds in thatthe disaggregant phenomenon is accompanied by hypotension) the 15-epianalogues, e.g. d,l-15-epi-PGI₂, have a moderate and prolongedhypertensive effect, making them ideal anti-thrombic agents for electiveuse in treating acute myocardial infaction.

The 15-epi-13,14-dehydro-derivatives also show a similar spectrum ofactivity.

A typical compound of this series is the15-epi-13,14-dehydro-20-methyl-PGI₂.

When compared with PGI₂ it appears as a PGI₂ like compound completelydeprived of the ability to contract the bovine coronary artery, the ratcolon and the stomach strips, whereas its ability in relaxing the bovinecoronary artery strips is approximately 15% of that of PGI₂.

In reversing the platelet aggregation induced by 2 μM ADP in rabbitplatelet rich plasma and in cat heparinized blood the IC₅₀ values(ng/ml) for 15-epi-13,14-dehydro-20-methyl-PGI₂ are respectively 75 and100 the corresponding values for PGI₂ being 3.9 and 1.

The tilted compound 15-epi-13,14-dehydro-20-methyl-PGI₂ is also devoidof any systemic hypotensive effect.

The compounds covered by this invention are prepared with a procedurebased on the dehydrohalogenation of a compound of formula (II) ##STR10##wherein R, p, q, R₁, Y, R₂, R₅, n₁, R₃, R₄, X, n₂ and R₆ are as definedabove and Z₂ is a halogen atom, preferably chlorine, bromine or iodineand, if desired, the dehydrohalogenation product of formula (I) may beconverted into another compound of formula (I), and/or, if desired,transformed to its salt, and/or, if desired, separated into itsindividual isomers.

The dehydrohalogenation is preferably run in an inert solvent with anappropriate dehydrohalogenating agent, and the solvent is preferablychosen from the group: dimethylsulfoxide, dimethylformamide,hexamethylphosphoramide, a linear or cyclic ether like dimethoxyethane,tetrahydrofuran, or dioxane, an aromatic hydrocarbon like benzene ortoluene, liquid ammonia. These solvents may also be used in mixtures andat temperatures ranging from the liquefaction point of ammonia to theboiling point of water, although room temperature is particularlypreferred.

The dehydrohalogenating agent is a base chosen preferably from: sodiumdimethylsulfinyl carbanion, potassium dimethylsulfinyl cabanion,diazabicycloundecene, diazabicyclononene, and an alkaline metal amide oralcoholate. The quantity of dehydrohalogenating base used in thereaction may vary from 1 to 5 moles per mole of compound, but thepreferred ratio is from 1.5-1.8 moles of base per mole of compound (II).

As a function of the solvent, the temperature, the molar ratio ofreagents and the nature of the halogenated substrate, the reaction timemay range from 20-30 minutes to 3-4 days.

The reactivity of the halogenated substrate decreases from iodide tobromide to chloride.

Particularly preferred reaction conditions involve the use ofdiazabicycloundecene as dehydrohalogenating agent at room temperature ina solvent like dimethylformamide or dimethylsulfoxide. When the desiredreaction product (I) has Y═-CH═CZ₁ -- where Z₁ is halogen, theseconditions allow selective dehydrohalogenation with no triple bondformation in position 13,14.

Satisfactory reaction conditions include the use of potassium alcoholate(preferably tert-butylate) or sodium or potassium dimethylsulfinylcarbanion in dimethylsulfoxide at room temperature, as well as that ofan alkali or alkaline earth alcoholate in a low molecular weightanhydrous alcohol. In the latter case, as the base strength of thecation decreases, the quantity of base needed to effectdehydrohalogenation increases proportionately.

The dehydrohalogenation reaction normally gives a mixture of the E and Zisomers which may in turn be separated by fractional crystallization orcolumn chromatography Fractional crystallization from a solvent likeethyl ether or a hydrocarbon like n-pentane, n-hexane, or cyclohexane ispreferred.

The optional transformation of a compound (I) into another with formula(I), the formation of a salt of formula (I), and the separation of themixture into individual isomers are run using standard procedures.However, the enol-ether structure of the compounds covered by thisinvention makes them very sensitive to acids, the optionaltransformation listed above must be effected under mild conditions,preferably neutral or basic.

In fact acid medium catalyzes the addition of water across theexo-cyclic double bond to give hemi-acetal (III) from compound (I).(III) is in turn in equilibrium with hydroxyketone (IV), ##STR11##wherein the substituents are as defined above.

When the enol ether in (I) is too acid-sensitive, the desiredtransformations may be run on the starting material, compound (II).

For instance, a compound of formula (I) or, preferably, a compound offormula (II), wherein R is --COOH gives one of formula (I) or (II)wherein R is --CH₂ OH upon reduction of the acid or its ester (preparedperhaps by reaction with an aliphatic alcohol in the presence of an acidcatalyst like p-toluenesulfonic acid) with LiAlH₄ in diethyl ether ortetrahydrofuran at reflux. Or compounds wherein R is --COOH can givederivatives wherein R is ##STR12## upon reaction of the hydrochloride ofthe carboximidic ester of the acid with an appropriate alcohol, asdescribed for instance in J. Amer. Chem. Soc., 64, 1827 (1942).

When R in the compounds of formula (I) or, preferably, in the compoundsof formula (II), is --COOH, a derivative in which R is ##STR13## whereinR_(a) and R_(b) are as defined above, can be prepared, for instance, bytreatment with an amine of formula NHR_(a) R_(b) in the presence of acondensing agent like a carbodiimide, for exampledicyclohexylcarbodiimide. Or, in the compounds of formula (I) or,preferably, in the compounds of formula (II), an R group of --COOH maybe converted to R═--C.tbd.N by transforming the carboxyl to thecorresponding acyl halide (preferably chloride), for instance byreaction with thionyl chloride in dioxane or dichloroethane at reflux,and then reacting the halide with ammonia to give the amide anddehydrating to give the nitrile. In turn, compounds of formula (I) or,preferably, of formula (II) with R═--C.tbd.N can give compounds offormula (I) or (II) wherein R is ##STR14## upon reaction with sodiumazide and ammonium chloride in dimethylformamide, at temperaturesranging from room temperature to approximately 100° C.

When R₁ is hydroxy in compounds of formula (I) or (II), this can beconverted to C₁ -C₆ alkoxy or aryl-C₁ -C₆ -alkoxy with commonetherification procedures like reaction with an optionally arylsubstituted diazoalkane in the presence of an acid catalyst (forinstance fluoroboric acid or boron trifluoride) in an organic solventlike dichloromethane. Another alternative is the reaction of thehydroxyl (free or as a salt) with an alkyl or arylalkyl halide in thepresence of a base like Ag₂ O in a solvent like dimethylsulfoxide ordimethylformamide.

Following the same procedure, a compound (I) or (II) in which R₅ ishydrogen gives the corresponding (I) or (II) where R₅ is C₁ -C₆ alkyl oraryl-C₁ -C₆ alkyl.

A compound of formula (I) in which R₁ is hydroxy may be transformed toone in which R₁ is acyloxy by using conventional methods, for instancetreatment with an anhydride or halide (like the chloride of anappropriate carboxylic acid) in the presence of a base.

In order to selectively etherify or esterify only one of several freehydroxyl groups in a molecule (for instance, in transforming compound(I) or (II) where R₁ is --OH and R₅ is hydrogen into the derivative inwhich R₁ is C₁ -C₆ alkoxy or aryl-C₁ -C₆ alkoxy or acyloxy and R₅ ishydrogen, or into that in which R₁ is hydroxy and R₅ is C₁ -C₆ alkyl oraryl-C₁ -C₆ -alkyl), the hydroxyl function to be unchanged must besuitably protected before the reaction with a known protecting group,which is then removed at the end of the reaction.

These protecting groups, generally ethers, are ones which may beconverted back to hydroxyl under mild reaction conditions: for example,acetal ethers, enol ethers and silyl ethers. Preferred protecting groupsare: ##STR15## where W is --O-- or --CH₂ -- and Alk is C₁ -C₆ alkyl.

Protecting groups may be removed from compounds of formula (II) withlike acid hydrolysis: for example, with mono- or poly-carboxylic acidslike formic, acetic, oxalic, citric, tartaric, in a solvent like water,acetone, tetrahydrofuran, dimethoxyethane, or a low molecular weightalcohol, or with a sulfonic acid like p-toluenesulfonic in a lowmolecular weight aliphatic alcohol like anhydrous methyl or ethyl, orwith a polystyrene-sulfonate resin.

On the other hand, protecting groups must be removed from compounds offormula (I) under neutral conditions: for instance, with F⁻ ions intetrahydrofuran when silyl ether groups are used.

If R₁ in compounds of formula (I) or (II) is an acyloxy group, it may betransformed to hydroxy by saponification with alkali, eliminating asmuch as possible prolonged contact with water for compounds (I).

A compound (I) or (II) in which Y is a --Ch═CZ₁ -- group where Z₁ ishalogen may be converted into the derivative in which Y is a --C.tbd.C--group by dehydrohalogenation. This may be effected, for instance, bytreatment with a dehydrohalogenating agent chosen from the group:dimethylsulfinyl carbanion (CH₃ SOCH₂ ⁻), diazabicycloundecene,diazabicyclononene, and an alkali metal or alcoholate in an inertsolvent under reactions conditions similar to those described fortransforming compound (II) into compound (I).

Salt formation for a compound (I) or (II) is done in the conventionalmanner, as is the optional separation of isomer mixtures: into opticalantipodes, into diastereomers, or into geometric isomers. For example,optical antipodes may be separated from a racemic mixture by saltformation with optically active compounds; diastereomers may beseparated through fractional crystallization or chromatography.

Fractional crystallizations are run in solvents like ethyl ether or analiphatic hydrocarbon like n-pentane or n-hexane. Both preparative thinlayer and column chromatography may be used, on silica gel or magnesiumsilicate with an eluent like dichloromethane, diethyl ether, isopropylether, ethyl acetate, benzene, methyl acetate or cyclohexane, as well asmixtures of them.

Diastereomers of compound (II) are preferably the only ones separated bychromatography since the weakly acidic chromatographic support (silicagel or magnesium silicate) can catalyze the formation of compounds (III)and (IV) from enol ethers (I).

Compounds of formula (II) are prepared halocyclizing a compound offormula (V) ##STR16## wherein p, q, Y, R₂, n₁, R₃, R₄, X, n₂ and R₆ areas defined above; D is a cis or trans double bond; R"' is (a") --COOR'wherein R' is as defined above; (b") --CH₂ --R'^(v) , wherein R'^(v) ishydroxy or a known protecting group bound to --CH₂ -- through an etherlinkage; (c") ##STR17## wherein each of R" is as defined above; (d")##STR18## wherein R_(a) and R_(b) are as defined above; (e") a ##STR19##radical; (f") --C.tbd.N; R'₁ is hydrogen, hydroxy, C₁ -C₆ alkoxy,aryl-C₁ -C₆ -alkoxy, acyloxy or a known protecting group bound to thering an ether linkage; and R'₅ is hydrogen, C₁ -C₆ alkyl, aryl-C₁ -C₆-alkyl or the residue of a known protecting group as defined above andremoving, by known methods, the protecting groups, when present.

The halocyclization may be run with a stoichiometric quantity or a smallexcess of halogenating agent in an inert solvent, both with or withoutbase. Preferred halogenating agents include iodine, bromine, chlorine,bromodioxane, bromopyridine, Br₂ -pyridine-HBr, KI₃,pyrrolidonehydrotribromide, an N-haloamide like N-chlorosuccinimide,N-bromosuccinimide, a copper halide like CuCl₂ or Cubr₂, a mixed halidelike ICl or IBr, and mixtures of an alkali chloride with alkalichlorate, of alkali bromide with alkali bromate, or of alkali iodidewith alkali iodate. Appropriate solvents include halogenatedhydrocarbons like CHCl₃, CCl₄, CH₂ Cl₂ ; aliphatic and cycloaliphatichydrocarbons like n-hexane, n-heptane and cyclohexane; aromatichydrocarbons like benzene, toluene and pyridine; cyclic or linear etherslike dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane; as wellas mixtures of them. However, the preferred solvents are halogenatedhydrocarbons like CH₂ Cl₂, since both compound (V) and the halogenatingagent are usually soluble in these solvents.

When a hydrohalide acid forms during the halocyclization reaction, astoichiometric quantity of a base must be present, either inorganic(like an oxide, carbonate or bicarbonate of an alkali or alkaline earthmetal: e.g., CaO, CaCO₃, K₂ CO₃) or organic (for instance, a tertiaryamine like triethylamine, or an aromatic one like substituted orunsubstituted pyridine, or an anionic-type ion exchange resin).

The halocyclization may be run at temperatures ranging from -70° C. to100° C., although room temperature is preferred. The reaction timevaries from a few minutes to several days, but is usually no more thantwo hours; often just a few minutes is sufficient.

When compound (V) contains other unsaturated bonds in addition to thatrepresented by D, these may also suffer addition during thehalocyclization. However, this addition product can easily be convertedto the original unsaturation by treatment with an alkali or alkalineearth iodide in an appropriate solvent (like acetone) at a temperaturevarying from room temperature to reflux, although the former ispreferred. Reaction time may run from 2-3 hours to 2-3 days.

Compounds (V) are known compounds and may be prepared as described inthe following:

E. J. Corey et al., Ann of New York Acad. of Sciences, 180,24(1971);

J. Fried et al., J. Med. Chem., 16,429(1973);

G. L. Bundy et al., J. Amer. Chem. Soc., 94,2124(1972);

Gandolfi et al., II Farmaco Ed. Sc., 27, 1125(1972);

J. S. Bindra & R. Bindra, Prostaglandins Synthesis, New York(1977);

U.S. Pat. Nos. 3,935,254 and 4,041,064;

German Offenlegungsschrift No. 26 11 788 (Derwent-Farmdoc 61615 X);

German Offenlegungsschrift No. 26 10 503 (Derwent-Farmdoc 59715 X);

German Offenlegungsschrift No. 26 27 422 (Derwent-Farmdoc 85028 X);

German Offenlegungsschrift No. 23 22 673 (Derwent-Farmdoc 73279 U);

German Offenlegungsschrift No. 21 54 309 (Derwent-Farmdoc 31279 T);

German Offenlegungsschrift No. 24 40 919 (Derwent-Farmdoc 19594 W);

U.S. Pat. Nos. 3,706,789; 3,728,382; 3,903,131; 3,962,293; 3,969,380;3,890,372; 3,636,120; 3,883,513; 3,932,389; 3,932,479; 4,021,477;4,029,681; and British Pat. No. 1,483,880.

The compounds covered by this invention may be used in human orveterinary medicine when natural prostaglandins are therapeuticallyindicated, with the advantages of greatly reduced metabolism rates andof more selective therapeutic action.

For instance, these compounds are useful in treating asthma since theyare strong bronchodilators; to this end, they may be administered inmany ways: orally (as tablets, capsules or pills; in drops or syrups),rectally (as suppositories); intravenously, intramuscularly, orsubcutaneously; by inhalation (in an aerosol or in vaporizer solutions);or by insufflation (as powder). Doses of approximately 0.01-4 mg/kg maybe given from 1 to 4 times daily, with the exact dose depending on theage, weight and condition of the patient as well as the method ofadministration. For anti-asthmatic applications, the compounds coveredby this invention may be given in combination with other anti-asthmaticagents: for instance, sympaticomimetics like isoproterenol, ephedrine,etc.; xanthine derivatives like theophylin and aminophylin; andcorticosteroids like prednisolone and ACTH.

Furthermore, the compounds covered by this invention show oxytocicactivity: that is, they may be used in place of oxytocin to induce laboror the expulsion of a dead fetus, in human as well as veterinarymedicine. In this application the compounds are administered either byintravenous infusion at a dose of approximately 0.01 μg/kg/minute untillabor is finished, or by mouth.

In addition, these compounds show luteolytic activity and are thereforeuseful for fertility control. In contrast to natural prostaglandins,they offer the advantage of a very reduced capacity to stimulate thesmooth muscles, with a resultant lack of side effects like vomiting anddiarrhea.

The pronounced anti ulcerogenic effect of these compounds leads to theirapplication in mammals to reduce and control excessive gastricexcretion, and so to block the formation of gastrointestinal ulcers andto accelerate the cure of any ulcers already present. To this end, thecompounds may be given by intravenous infusion or by intravenous,subcutaneous or intramuscular injection. In an infusion, the dose variesfrom approximately 0.1 μg to 500 μg per kilogram body weight perminutes. The total daily dose, for both injection and infusion, isapproximately 0.1-20 mg/kg, depending both on the patient's or animal'sage, weight and condition and on the method of administration.

However, as discussed previously, the most important pharmacologicalactivity of the compounds covered by this invention is their plateletanti-aggregant action: that is, their capacity to inhibit plateletaggregation by decreasing adhesiveness, to prevent the formation ofthrombi and clots, and above all to dissolve already formed thrombi andclots in mammals. Further, they exhibit no hypotensive side effects.

The compounds may thus be used in preventing and treating bothconditions of hyperlypidemia, like atherosclerosis and arteriosclerosis;and above all myocardial infarctions, since, as discussed above, theantithrombotic and thrombolytic activity of these compounds is notassociated with any systemic hypotensive effect.

The above conditions may be treated with the normal methods ofadministration: that is, intravenously, subcutaneously, intramuscularly,etc., in doses ranging from 0.005 to 20 mg/kg/day, depending on the age,weight and condition of the patient as well as on the administrationmethod. In emergency situations, intravenous administration ispreferred. Owing to their antithrombotic and thrombolytic activitieswhich are not associated with any systemic hypotensive-effect, thecompounds of the invention can be used during haemodialysis andextracorporeal haemoperfusion in man. So infusion of aqueous solutionsof salts, e.g. alkaline salts, of 15-epi-prostacyclins in dosesequivalent to 30-150 ng/kg/min. in the dialyser inlet line and continuedat the same rate throughout dialysis, reduces blood-artificial surfaceinteraction and allow dialysis to be executed without thrombocytopeniaand microembolization occurring. At present heparin is used duringhaemodialysis to prevent gloss/clotting of blood. In spite of that,interaction between coagulation factors, blood cells and the artificialsurfaces of the dialyser and lines occurs having thrombus deposition andintradialyser blood loss. These events can be minimised, the dialyserefficiency prolonged and the systemic circulating disturbance prevented,in presence or not of heparin, by addition of 15-epi-prostacyclins. Theuse of 15-epi-prostacyclins devoid of systemic hypotensive effect iscertainly preferable to that of the natural hormone.

As discussed above, the compounds covered by this invention may beadministered in many ways, depending on the application: intravenously,intramuscularly, subcutaneously, orally, endovaginally, rectally,topically.

Conventional excipients and carriers are used for the variouspharmaceutical formulations. For oral administration, some examples are:lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearicacid, calcium or magnesium stearate, glycol, amides, gum arabic, gumadragant, alginic acid or alginates, lecithin, polysorbates,laurylsulfates, etc. For administration with a vaporizer, one uses asuspension or solution of the compound (preferably as a salt like thesodium derivative) in water. Alternatively, the pharmaceuticalformulation may be a suspension or solution of the compound in a commonliquified propellant like dichlorodifluoromethane ordichlorotetrafluoroethane to be administered from a pressurizedcontainer like an aerosol bomb. If the compound is not soluble in thepropellant, a cosolvent may be added (like ethanol or dipropylenicclycol) and/or a tensio active/substance. For parenteral administration,the compound may be dissolved, for example, in sterile water, in alydocain hydrochloride or physiological saline solution, in a dextrosesolution or in one of the other standard solvents used in this type ofadministration.

The following examples illustrate this invention without limiting it inany way.

EXAMPLE 1

A solution of 0.7 g ofdl-9-deoxy-5-iodo-6βH-6,9α-oxide-11α,15R-dihydroxy-prost-13-trans-enoicacid methyl ester in 30 ml of methanol and 5 ml of water is treated for6 hours at room temperature with 0.3 g of lithium hydrate. After removalof the excess methanol, the aqueous solution is extracted with ethylether to remove any neutral impurities; it is then acidified to pH 5.2and extracted repeatedly with freshly-distilled ethyl ether. Thecombined organic extract is dried and evaporated to give 0.675 g ofdl-9-deoxy-5-iodo-6βH-6,9α-oxide-11α,15R-dihydroxy-prost-13-trans-enoicacid, which is dissolved in 10 ml of t-butanol and treated with 0.4 g ofpotassium t-butylate at 45° C. for 3 hours. The potassium iodideprecipitate is separated by filtration, and the filtrate is evaporatedto dryness to give a residue of 0.545 g of the potassium salt ofdl-15-epi-PGI₂ (C₂₀ H₃₁ O₅ K, 390.55 g/mol).

I.R. (KBr): λ_(max) =1692 cm⁻¹ ##STR20## ¹³ C N.M.R.: 182.5 (C-1); 158.1(C-6); 139.8 and 134.3 (C 13-14); 100.5 (C-5); 87.0 (C-15); 80.6 and75.6 (C 9-11); 58.1 (C-12); 49.0, 45.7, 42.5, 41.7, 37.6, 35.8 (C-18);31.6, 29.4, 26.6 (C-19); 18.3 (C-20) ppm from TMS in DMSO.

A sample of this (0.18 g) is dissolved in water (0.6 ml). The pH is thenadjusted to 7.0 with 2 N sulfuric acid, 20% monobasic phosphate isadded, and the mixture if held at pH 4.9 for 20 minutes. The aqueoussolution is then extracted with ethyl acetate; the organic phase yields0.050 g of dl-15-epi-6-keto-PGF₁ α.

Following the same procedure, nat- andent-9-deoxy-5-iodo-6βH-6,9α-oxide-11α,15R-dihydroxy-prost-13-transenoicacid give, respectively: nat-15-epi-PGI₂ ; ent-15-epi-PGI₂.

EXAMPLE 2

A solution of 110 mg ofdl-9-deoxy-5-iodo-6αH-6,9α-oxide-11α,15R-dihydroxy-prost-13-trans-enoicacid methyl ester is hydrolyzed following the procedure in the precedingexample (3 ml methanol, 0.5 ml water, 30 mg LiOH) to give 98 mg of thefree acid. 88.3 mg of this are dissolved in 2 ml of tert-butanol andtreated at room temperature with 83 mg of potassium t-butylate. This isheld for 5 hours at room temperature to effect completedehydrohalogenation. Work-up of the mixture as in the preceding examplegives 68 mg of the potassium salt of dl-15-epi-5E-PGI₂. I.R. (KBr):λ_(max) =1692 cm⁻¹ ##STR21##

Similarly, from the single isomers, the following were obtained:

nat-15-epi-5E-PGI₂ ;

ent-15-epi-5E-PGI₂.

An aqueous solution of 80 mg of the potassium salt of dl-15-epi-5E-PGE₂is brought to pH 4.8 with a saturated solution of monosodium phosphateand held for four hours at 30° C. Repeated extraction with ethyl acetateand evaporation of the organic phase give 51 mg ofdl-6-keto-15-epi-PGF₁, identical in all respects with that preparedaccording to the preceding example.

EXAMPLE 3

1.2 g of5-bromo-6αH-9-deoxy-6,9α-oxide-11α,15R-dihydroxy-prost-13-trans-enoicacid methyl ester in 18 ml of methanol is saponified by the addition of0.18 g of lithium hydroxide in 1.8 ml of water. After 8 hours at roomtemperature, the solvent is evaporated and water is added. The aqueoussolution is extracted with ethyl acetate and the extract discarded. Theaqueous phase is acidified to pH 4.8 and extracted with 5:1 ethyl ether:methylene chloride. Drying and removal of solvent afford 1.08 g of the5-bromo acid. A solution of this in 20 ml of tert-butanol is treatedwith 1.3 g of freshly sublimed potassium butylate. The reaction mixtureis heated for 90 minutes at 50° C., cooled, separated from the KBrprecipitate by filtration, and evaporated to give 0.9 g of the15-epi-PGI₂ potassium salt. I.R. (KBr) λ_(max) =1692 cm⁻¹ ##STR22## Whentreated as the enant-ester, the dl-bromo derivatives gave:dl-15-epi-PGI₂ ;

ent-15-epi-PGI₂.

EXAMPLE 4

A solution of 0.4 g of 11,15-diepi-PGF₂α -methyl ester in 8 ml of ethylether is emulsified with 12 ml of saturated sodium bicarbonate. Withstirring and cooling to 0.2° C., a solution of iodine in ethyl ether isadded (12.5 ml, I₂ concentration=25 mg/ml). Stirring is continued foranother 8 hours, and the organic phase is separated and washedrepeatedly with 0.1 N Na₂ S₂ O₃. Drying and removal of solvent give aresidue which is purified on SiO₂ (ethyl ether as eluent) to give 340 mgof pure 6αH-5-iodo-11,15-diepe-5,6α-dihydro-PGI₂ methyl ester. 300 mg ofthis are reacted at room temperature with a solution of sodium methylatein anhydrous methanol prepared by dissolving 0.14 g of Na in 2.5 ml ofMeOH. Complete dehydrohalogenation is achieved in 12 hours at roomtemperature to give 11,15-diepi-PGI₂ -methyl ester. The reaction isfollowed by thin layer chromatography on silica gel and florisil, withethyl acetate:triethylamine (100:2) as eluent. The methyl ester solutionis then diluted with 1.5 ml of an aqueous solution of 1.0 N sodiumhydroxide; hydrolysis is complete after 2 hours. Removal of the solventaffords a residue of the crude sodium salt of 11,15-diepi-PGI₂, to whicha few drops of 1 N NaOH are added. After a few hours of refrigeration, acrystalline product separates which is collected by centrifugation togive 68 mg of pure nat-11,15-diepi-PGI₂ sodium salt. IR(KBr) λ_(max)=1692 cm⁻¹ ##STR23##

Ent-11,15-diepi-PGF₂α gives ent-11,15-diepi-PGI₂ sodium salt by the sameprocedure.

EXAMPLE 5

Following the procedure of example 4, one obtains6β-H-5-iodo-9-deoxy-6,9β-oxide-11β,15R-dihydroxy-20-methylprost-13-inoicacid methyl ester from 15-epi-5-cis-20-methyl-13,14-dehydro-PGF₂α methylester. 1 g of this product is stirred overnight under nitrogen with asodium methylate solution prepared by dissolving 0.5 g of sodium in 7.5ml of methanol. The resulting yellow solution is diluted with 5 ml of 1N sodium hydroxide and the methyl ester of20-methyl-15-epi-13,14-dehydro-PGI₂ is completely hydrolyzed after 4hours. The methanol is removed under vacuum, and, upon cooling, thesodium salt precipitates from the aqueous solution. It is isolated byfiltration and dried under vacuum to give 0.485 g of20-methyl-15-epi-13,14-dehydro-PGI₂ sodium salt. [α]_(D) =+72.4 (EtOH);IR (KBr): λ_(max) =1696 cm⁻¹ ##STR24##

A 100 mg sample of this product dissolved in water, acidified withsaturated monosodium phosphate and extracted gives 0.058 g of20-methyl-15-epi-13,14-dehydro-6-keto-PGF₁α.

Proceeding analogously, 15-epi-13,14-dehydro-PGI₂ sodium salt wasobtained.

EXAMPLE 6

0.3 g of 1,5-diazabycicloundecene is added to a solution of 0.5 g of13t-5-iodo-6βH-6,9α-oxide-20-methyl-11α,15R-dihydroxy-prost-13-enoicacid methyl ester in 2.5 ml of anhydrous dimethylformamide; theresulting mixture is held at 60° C. for 8 hours. The solution is dilutedwith 10 ml of water and extracted repeatedly with 1:1 ethylether:pentane. The combined organic phase is washed with cold water,with cold 5.1 pH buffer, and then with water until neutral. Afterdrying, removal of the solvent affords 0.32 g of 15-epi-20-methyl-PGI₂methyl ester, I.R. (KBr): λ_(max) =1735 cm⁻¹ (CO₂ CH₃) and λ_(max) =1695cm⁻¹ ##STR25## which is then saponified to give the sodium salt. Fromthe analogous dl-5-iodo-dimethylamide derivative, thedl-15-epi-20-methyl-PGI₂ dimethylamide is prepared.

EXAMPLE 7

180 mg of potassium t-butylate is added to a solution of 250 mg of13t-5,14-dibromo-6βH-6,9α-oxide-15R-methoxy-16S-methyl-prostenoic acidin 4.4 ml of dimethylsulfoxide; the resulting mixture is held for 4hours under nitrogen with water excluded. The DMSO is removed undervacuum and the residue is taken up in 5:1 ethyl ether:dichloromethaneand a 6.8 pH buffer while keeping the temperature at 0°-2° C. Thecombined organic phase is dried and evaporated (and the residueconverted to its triethylamine salt) to give 0.105 g of15R-methoxy-16S-methyl-11-deoxy-13,14-dehydro-PGI₂. I.R. (KBr): λ_(max)=1694 cm⁻¹ ##STR26## By the same procedure15R-hydroxy-16S-methyl-11-deoxy-13,14-dehydro-PGI₂ was obtained.

EXAMPLE 8

A stirred solution of 2.5 g (5.06×10⁻¹ mol) ofdl-13t-20-methyl-5-iodo-6βH-6,9α-oxide-11α,15R-dihydroxy-prost-13-enoicacid in 12 ml of anhydrous methanol is treated at room temperature with3 g of sodium methylate for 6 hours under nitrogen. The solvent is thenevaporated and the dry residue taken up in 2 ml of 1 N NaOH; uponcooling, a crystalline product forms which is isolated by filtration togive the sodium salt of dl-20-methyl-15-epi-PGI₂.

I.R. (KBr): λ_(max) =1690 cm⁻¹ ##STR27## ¹³ C N.M.R.: 182.7 (C-1); 158.5(C-6); 140.2 and 134.4 (C-13,14); 100.7 (C-5); 87.0 (C-15); 80.5 and75.8 (C-9,11); 58.3 (C-12); 48.8, 45.8, 42.5, 41.8, 37.5, 35.7 (C-18);31.6, 29.8, 29.2, 26.5 (C-19); 29.8, 28.2, 27.5, 24.2 (C-20); 18.3(C-21) ppm from T.M.S. in DMSO-d₆.

In an analogous fashion, from the corresponding 5-iodo-6,9-oxides, thefollowing compounds are prepared as their sodium salts (natural and d,l15-epi):

20-methyl-15-epi-PGI₂ ;

20-ethyl-15-epi-PGI₂ ;

16S-methyl-15-epi-PGI₂ ;

16R-methyl-15-epi-PGI₂ ;

16S-fluoro-15-epi-PGI₂ ;

16R-fluoro-15-epi-PGI₂ ;

16(S,R)-fluoro-15-epi-PGI₂ ;

16S,20-dimethyl-15-epi-PGI₂ ;

16R,20-dimethyl-15-epi-PGI₂ ;

15-methyl-15-epi-PGI₂ ;

17-oxa-15-epi-PGI₂ ;

20 methyl-17-oxa-15-epi-PGI₂ ;

16,16-dimethyl-17-oxa-15-epi-PGI₂ ;

16,16-dimethyl-15-epi-PGI₂ ;

16,16,20-trimethyl-17-oxa-15-epi-PGI₂ ;

16,16-dimethyl-20-ethyl-17-oxa-15-epi-PGI₂ ;

ω-nor-19-cyclohexyl-15-epi-PGI₂ ;

ω-bisnor-18-cyclohexyl-15-epi-PGI₂ ;

ω-trinor-17-cyclohexyl-15-epi-PGI₂ ;

ω-trinor-16(S),(R)- and (S,R)-fluoro-17-cyclohexyl-15-epi-PGI₂ ;

ω-trinor-17-phenyl-15-epi-PGI₂ ;

ω-trinor-17-cyclopentyl-15-epi-PGI₂ ;

ω-trinor-17-(2'-norbornyl)-15-epi-PGI₂ ;

ω-trinor-17-(2'-tetrahydrofuryl)-15-epi-PGI₂ ;

ω-trinor-17-(2'-furyl)-15-epi-PGI₂ ;

ω-tetranor-16-cyclohexyl-15-epi-PGI₂ ;

ω-tetranor-16-phenyl-15-epi-PGI₂ ;

ω-tetranor-16-phenoxy-15-epi-PGI₂ ;

ω-tetranor-16-p-fluorophenoxy-15-epi-PGI₂ ;

ω-tetranor-16-p-chlorophenoxy-15-epi-PGI₂ ;

ω-tetranor-16-m-chlorophenoxy-15-epi-PGI₂ ;

ω-tetranor-16-m-trifluoromethylphenoxy-15-epi-PGI₂ ;

ω-tetranor-16-(2'-norbornyl)-15-epi-PGI₂ ;

ω-tetranor-16-butoxy-15-epi-PGI₂ ;

ω-trinor-16-methyl-16-butoxy-15-epi-PGI₂ ;

ω-trinor-16-methyl-16-propoxy-15-epi-PGI₂ ;

ω-trinor-16-methyl-16-amyloxy-15-epi-PGI₂ ;

13,14-dihydro-20-methyl-15-epi-PGI₂ ;

13,14-dihydro-15-epi-PGI₂ ;

13,14-dihydro-20-ethyl-15-epi-PGI₂ ;

13,14-dihydro-16S-methyl-15-epi-PGI₂ ;

13,14-dihydro-16R-methyl-15-epi-PGI₂ ;

13,14-dihydro-15-methyl-15-epi-PGI₂ ;

13,14-dihydro-16,16-dimethyl-17-oxa-15-epi-PGI₂ ;

13,14-dihydro-16,16-dimethyl-15-epi-PGI₂ ;

13,14-dihydro-16,16,20-trimethyl-17-oxa-15-epi-PGI₂ ;

13,14-dihydro-16,16-dimethyl-20-ethyl-17-oxa-15-epi-PGI₂ ;

13,14-dihydro-ω-nor-19-cyclohexyl-15-epi-PGI₂ ;

13,14-dihydro-ω-bisnor-18-cyclohexyl-15-epi-PGI₂ ;

13,14-dihydro-ω-trinor-17-cyclohexyl-15-epi-PGI₂.

13,14-dihydro-ω-trinor-17-phenyl-15-epi-PGI₂ ;

13,14-dihydro-ω-trinor-17-cyclopentyl-15-epi-PGI₂ ;

13,14-dihydro-ω-trinor-17-(2'-norbornyl)-15-epi-PGI₂,

13,14-dihydro-ω-trinor-17-(2'-tetrahydrofuryl)-15-epi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-cyclohexyl-15-epi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-phenyl-15-epi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-phenoxy-15-epi-PGI₂ ;

13,14-dihydro-107 -tetranor-16-p-fluorophenoxy-15-epi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-m-chlorophenoxy-15-epi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-m-trifluoromethylphenoxy-15-epi-PGI₂ ;

13,14-dehydro-15-epi-PGI₂ ;

13,14-dehydro-20-methyl-15-epi-PGI₂ ;

13,14-dehydro-20-ethyl-15-epi-PGI₂ ;

13,14-dehydro-16S-methyl-15-epi-PGI₂ ;

13,14-dehydro-16R-methyl-15-epi-PGI₂ ;

13,14-dehydro-16(S,R)-methyl-15-epi-PGI₂ ;

13,14-dehydro-16S,20-methyl-15-epi-PGI₂ ;

13,14-dehydro-15-methyl-15-epi-PGI₂ ;

13,14-dehydro-ω-nor-19-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ω-bisnor-18-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ω-trinor-17-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ω-trinor-16(S),(R)- and(S,R)-fluoro-17-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ω-trinor-17-phenyl-15-epi-PGI₂ ;

13,14-dehydro-ω-trinor-17-cyclopentyl-15-epi-PGI₂ ;

13,14-dehydro-ω-trinor-17-(2'-norbornyl)-15-epi-PGI₂ ;

13,14-dehydro-ω-trinor-17-(2'-tetrahydrofuryl)-15-epi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-phenyl-15-epi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-phenoxy-15-epi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-p-fluorophenoxy-15-epi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-m-chlorophenoxy-15-epi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-m-trifluoromethylphenoxy-15-epi-PGI₂ ;

as well as:

ent-20-methyl-15-epi-PGI₂ ;

ent-20-ethyl-15-epi-PGI₂ ;

ent-16S-methyl-15-epi-PGI₂ ;

ent-16R-methyl-15-epi-PGI₂ ;

ent-16S-fluoro-15-epi-PGI₂ ;

ent-16R-fluoro-15-epi-PGI₂ ;

ent-16(S,R)-fluoro-15-epi-PGI₂ ;

ent-16S,20-dimethyl-15-epi-PGI₂ ;

ent-16R,20-dimethyl-15-epi-PGI₂ ;

ent-15-methyl-15-epi-PGI₂ ;

ent-17-oxa-15-epi-PGI₂ ;

ent-20-methyl-17-oxa-15-epi-PGI₂ ;

ent-16,16-dimethyl-17-oxa-15-epi-PGI₂ ;

ent-16,16-dimethyl-15-epi-PGI₂ ;

ent-16,16,20-trimethyl-17-oxa-15-epi-PGI₂ ;

ent-16,16-dimethyl-20-ethyl-17-oxa-15-epi-PGI₂ ;

ent-ω-nor-19-cyclohexyl-15-epi-PGI₂ ;

ent-ω-bisnor-18-cyclohexyl-15-epi-PGI₂ ;

ent-ω-trinor-17-cyclohexyl-15-epi-PGI₂ ;

ent-ω-trinor-16(S),(R)- and (S,R)-fluoro-17-cyclohexyl-15-epi-PGI₂ ;

ent-ω-trinor-17-phenyl-15-epi-PGI₂ ;

ent-ω-trinor-17-cyclopentyl-15-epi-PGI₂ ;

ent-ω-trinor-17-(2'-norbornyl)-15-epi-PGI₂ ;

ent-ω-trinor-17-(2'-tetrahydrofuryl)-15-epi-PGI₂ ;

ent-ω-trinor-17-(2'-furyl)-15-epi-PGI₂ ;

ent-ω-tetranor-16-cyclohexyl-15-epi-PGI₂ ;

ent-ω-tetranor-16-phenyl-15-epi-PGI₂ ;

ent-ω-tetranor-16-phenoxy-15-epi-PGI₂ ;

ent-ω-tetranor-16-p-fluorophenoxy-15-epi-PGI₂ ;

ent-ω-tetranor-16-p-chlorophenoxy-15-epi-PGI₂ ;

ent-ω-tetranor-16-m-chlorophenoxy-15-epi-PGI₂ ;

ent-ω-tetranor-16-m-trifluoromethylphenoxy-15-epi-PGI₂ ;

ent-ω-tetranor-16-(2'-norbornyl)-15-epi-PGI₂ ;

ent-107 -tetranor-16-butoxy-15-epi-PGI₂ ;

ent-ω-trinor-16-methyl-16-butoxy-15-epi-PGI₂ ;

ent-ω-trinor-16-methyl-16-propoxy-15-epi-PGI₂ ;

ent-ω-trinor-16-methyl-16-amyloxy-15-epi-PGI₂ ;

13,14-dihydro-ent-20-methyl-15-epi-PGI₂ ;

13,14-dihydro-ent-15-epi-PGI₂ ;

13,14-dihydro-ent-20-ethyl-15-epi-PGI₂ ;

13,14-dihydro-ent-16S-methyl-15-epi-PGI₂ ;

13,14-dihydro-ent-16R-methyl-15-epi-PGI₂ ;

13,14-dihydro-ent-15-methyl-15-epi-PGI₂ ;

13,14-dihydro-ent-16,16-dimethyl-17-oxa-15-epi-PGI₂ ;

13,14-dihydro-ent-16,16-dimethyl-15-epi-PGI₂ ;

13,14-dihydro-ent-16,16,20-trimethyl-17-oxa-15-epi-PGI₂ ;

13,14-dihydro-ent-16,16-dimethyl-20-ethyl-17-oxa-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-nor-19-cyclohexyl-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-bisnor-18-cyclohexyl-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-trinor-17-cyclohexyl-15-epi-PGI₂.

13,14-dihydro-ent-ω-trinor-17-phenyl-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-trinor-17-cyclopentyl-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-trinor-17-(2'-norbornyl)-15-epi-PGI₂,

13,14-dihydro-ent-ω-trinor-17-(2'-tetrahydrofuryl)-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-tetranor-16-cyclohexyl-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-tetranor-16-phenyl-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-tetranor-16-phenoxy-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-tetranor-16-p-fluorophenoxy-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-tetranor-16-m-chlorophenoxy-15-epi-PGI₂ ;

13,14-dihydro-ent-ω-tetranor-16-m-trifluoromethylphenoxy-15-epi-PGI.sub.2;

13,14-dehydro-ent-15-epi-PGI₂ ;

13,14-dehydro-ent-20-methyl-15-epi-PGI₂ ;

13,14-dehydro-ent-20-ethyl-15-epi-PGI₂ ;

13,14-dehydro-ent-16S-methyl-15-epi-PGI₂ ;

13,14-dehydro-ent-16R-methyl-15-epi-PGI₂ ;

13,14-dehydro-ent-16(S,R)-methyl-15-epi-PGI₂ ;

13,14-dehydro-ent-16S,20-dimethyl-15-epi-PGI₂ ;

13,14-dehydro-ent-15-methyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-nor-19-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-bisnor-18-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-trinor-17-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-trinor-16(S),(R)- and(S,R)-fluoro-17-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-trinor-17-phenyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-trinor-17-cyclopentyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-trinor-17-(2'-norbornyl)-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-trinor-17-(2'-tetrahydrofuryl)-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-tetranor-16-cyclohexyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-tetranor-16-phenyl-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-tetranor-16-phenoxy-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-tetranor-16-p-fluorophenoxy-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-tetranor-16-m-chlorophenoxy-15-epi-PGI₂ ;

13,14-dehydro-ent-ω-tetranor-16-m-trifluoromethylphenoxy-15-epi-PGI.sub.2;

20-methyl-11,15-diepi-PGI₂ ;

20-ethyl-11,15-diepi-PGI₂ ;

16S-methyl-11,15-diepi-PGI₂ ;

16R-methyl-11,15-diepi-PGI₂ ;

16S-fluoro-11,15-diepi-PGI₂ ;

16R-fluoro-11,15-diepi-PGI₂ ;

16(S,R)-fluoro-11,15-diepi-PGI₂ ;

16S,20-dimethyl-11,15-diepi-PGI₂ ;

16R,20-dimethyl-11,15-diepi-PGI₂ ;

15methyl-11,15-diepi-PGI₂ ;

17-oxa-11,15-diepi-PGI₂ ;

20-methyl-17-oxa-11,15-diepi-PGI₂ ;

16,16-dimethyl-17-oxa-11,15-diepi-PGI₂ ;

16,16-dimethyl-11,15-diepi-PGI₂ ;

16,16,20-trimethyl-17-oxa-11,15-diepi-PGI₂ ;

16,16-dimethyl-20-ethyl-17-oxa-11,15-diepi-PGI₂ ;

ω-nor-19-cyclohexyl-11,15-diepi-PGI₂ ;

ω-bisnor-18-cyclohexyl-11,15-diepi-PGI₂ ;

ω-trinor-17-cyclohexyl-11,15-diepi-PGI₂ ;

ω-trinor-16(S),(R)- and (S,R)-fluoro-17-cyclohexyl-11,15-diepi-PGI₂ ;

ω-trinor-17-phenyl-11,15-diepi-PGI₂ ;

ω-trinor-17-cyclopntyl-11,15-diepi-PGI₂ ;

ω-trinor-17-(2'-norbornyl)-11,15-diepi-PGI₂ ;

ω-trinor-17-(2'-tetrahydrofuryl)-11,15-diepi-PGI₂ ;

ω-trinor-17-(2'-furyl)-11,15-diepi-PGI₂ ;

ω-tetranor-16-cyclohexyl-11,15-diepi-PGI₂ ;

ω-tetranor-16-phenyl-11,15-diepi-PGI₂ ;

ω-tetranor-16-phenoxy-11,15-diepi-PGI₂ ;

ω-tetranor-16-p-fluorophenoxy-11,15-diepi-PGI₂ ;

ω-tetranor-16-p-chlorophenoxy-11,15-diepi-PGI₂ ;

ω-tetranor-16-m-chlorophenoxy-11,15-diepi-PGI₂ ;

ω-tetranor-16-m-trifluoromethylphenoxy-11,15-diepi-PGI₂ ;

ω-tetranor-16-(2'-norbornyl)-11,15-diepi-PGI₂ ;

ω-tetranor-16-butoxy-11,15-diepi-PGI₂ ;

ω-trinor-16-methyl-16-butoxy-11,15-diepi-PGI₂ ;

ω-trinor-16-methyl-16-propoxy-11,15-diepi-PGI₂ ;

ω-trinor-16-methyl-16-amyloxy-11,15-diepi-PGI₂ ;

13,14-dihydro-20-methyl-11,15-diepi-PGI₂ ;

13,14-dihydro-11,15-diepi-PGI₂ ;

13,14-dihydro-20-ethyl-11,15-diepi-PGI₂ ;

13,14-dihydro-16S-methyl-11,15-diepi-PGI₂ ;

13,14-dihydro-16R-methyl-11,15-diepi-PGI₂ ;

13,14-dihydro-15-methyl-11,15-diepi-PGI₂ ;

13,14-dihydro-16,16-dimethyl-17-oxa-11,15-diepi-PGI₂ ;

13,14-dihydro-16,16-dimethyl-11,15-diepi-PGI₂ ;

13,14-dihydro-16,16,20-trimethyl-17-oxa-11,15-diepi-PGI₂ ;

13,14-dihydro-16,16-dimethyl-20-ethyl-17-oxa-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-nor-19-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-bisnor-18-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-trinor-17-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ωtrinor-17-phenyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-trinor-17-cyclopentyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-trinor-17-(2'-norbornyl)-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-trinor-17-(2'-tetrahydrofuryl)-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-phenyl-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-phenoxy-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-p-fluorophenoxy-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-m-chlorophenoxy-11,15-diepi-PGI₂ ;

13,14-dihydro-ω-tetranor-16-m-trifluoromethylphenoxy-11,15-diepi-PGI.sub.2;

13,14-dehydro-11,15-diepi-PGI₂ ;

13,14-dehydro-20-methyl-11,15-diepi-PGI₂ ;

13,14-dehydro-20-ethyl-11,15-diepi-PGI₂ ;

13,14-dehydro-16S-methyl-11,15-diepi-PGI₂ ;

13,14-dehydro-16R-methyl-11,15-diepi-PGI₂ ;

13,14-dehydro-16(S,R)-methyl-11,15-diepi-PGI₂ ;

13,14-dehydro-16S,20-dimethyl-11,15-diepi-PGI₂ ;

13,14-dehydro-15-methyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-nor-19-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-bisnor-18-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-trinor-17-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-trinor-16(S),(R)- and(S,R)-fluoro-17-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-trinor-17-phenyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-trinor-17-cyclopentyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-trinor-17-(2'-norbornyl)-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-trinor-17-(2'-tetahydrofuryl)-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-cyclohexyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-phenyl-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-phenoxy-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-p-fluorophenoxy-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-m-chlorophenoxy-11,15-diepi-PGI₂ ;

13,14-dehydro-ω-tetranor-16-m-trifluoromethylphenoxy-11,15-diepi-PGI.sub.2.

EXAMPLE 9

0.55 g of freshly sublimed potassium t-butylate is added to a solutionof 0.8 g of 5-chloro-6βH-6,9α-oxide-15R-hydroxy-prost-13-enoic acid in6.5 ml of dimethylsulfoxide. After 24 hours in an inert atmosphere, theDMSO is evaporated and the residue is partitioned between ethylether:pentane and a pH 6.8 buffer. The organic phase is dried andevaporated to give 0.52 g of 11-deoxy-15-epi-PGI₂, which is stored asits triethylamine salt.

I.R. (KBr): ν_(max) =1679 cm⁻¹ ##STR28##

Proceeding analogously, the following compounds were prepared:

11-deoxy-16S-methyl-15-epi-PGI₂ ;

11-deoxy-16,16-dimethyl-15-epi-PGI₂ ;

11-deoxy-16,16,20-trimethyl-17-oxa-15-epi-PGI₂ ;

11-deoxy-16,16-dimethyl-20-ethyl-17-oxa-15-epi-PGI₂.

EXAMPLE 10

280 mg of sodium t-butylate is added to a solution of 461 mg of13t-16S,20-dimethyl-5-bromo-6βH-6,9α-oxide-15-epi-prost-13-trans-enoicacid in 9 ml of anhydrous tert-butanol; the resulting mixture is held at40°-45° C. for 10 hours. After cooling, the solvent is evaporated undervacuum to give the sodium salt of 16S-20-dimethyl-15-epi-PGI₂ (sodiumbutylate and sodium bromide mixture). Crystalliwation from 2 N sodiumhydrate gives 0.21 g of pure product. I.R. (KBr): ν_(max) =1690 cm⁻¹##STR29##

In an analogous fashion, all of the compounds listed in example 8 wereprepared from the 5-bromo-6βH-6.9α-oxides.

We claim:
 1. A 15-epi compound of the formula (I) ##STR30## wherein R is--COOR' wherein R' is hydrogen or C₁ -C₆ alkyl;p is zero or an integerbetween 1 and 7; q is 1; R₁ is hydroxy, C₁ -C₆ alkoxy, benzyloxy,alkanoyloxy, or benzoyloxy; Y is --CH₂ --CH₂ --, ##STR31## (cis),##STR32## (trans) where Z₁ is hydrogen or halogen; R₂ is hydrogen, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, phenyl, tolyl, α-naphthyl orβ-naphthyl; R₅ is hydrogen, C₁ -C₆ alkyl, or benzyl; n₁ and n₂, whetherthe same or different, are 0 or an integer between 1 and 6; R₃ and R₄,whether the same or different, may be hydrogen C₁ -C₆ alkyl or fluorine,or may form a ##STR33## group with a carbon atom to which they arebound: X is chosen from --O--, --S--, and --(CH₂)_(m), where m is 0 or1; R₆ is a substituent chosen from (a') hydrogen, (b') C₁ -C₄ alkyl,(c') C₃ -C₉ cycloalkyl, C₃ -C₉ cycloalkyenyl, norbornyl or adamantylradical, optionally substituted with one or more C₁ -C₆ alkyl and C₁ -C₆alkoxy groups, (d') phenyl, tolyl, α-naphthyl or β-naphthyl, optionallysubstituted with one or more of halogen, C₁ -C₆ alkyl, halo-C₁ -C₆-alkyl or C₁ -C₆ -alkoxy; and a pharmacuetically or veterinarilyacceptable salt thereof, with the provisos that:(a) when X is--(CH₂)_(m) -- wherein m is as defined above, R' is hydrogen, Y is--CH═CH-- (trans) and R₆ is hydrogen or C₁ -C₄ alkyl then R₂ is not C₂-C₆ alkenyl; (b) when X is O and R₂ is hydrogen, C₁ -C₆ alkyl or C₂ -C₆alkenyl, R₆ is α-naphthyl or β-naphthyl, optionally substituted with oneor more of halogen, C₁ -C₆ alkyl, halo-C₁ -C₆ -alkyl or C₁ -C₆ -alkoxy;and (c) when X is S and R₂ is hydrogen, C₁ -C₆ alkyl or C₂ -C₆ alkenyl,R₆ is phenyl, tolyl, α-naphthyl or β-naphthyl, optionally substitutedwith one or more halogen, C₁ -C₆ alkyl, halo-C₁ -C₆ -alkyl or C₁ -C₆-alkoxy.
 2. A 15-epi compound of the formula (I) ##STR34## wherein R is--COOR' wherein R' is hydrogen;p is zero or an integer between 1 and 7;q is 1; R₁ is hydroxy, C₁ -C₆ alkoxy, benzyloxy, alkanoyloxy, orbenzoyloxy; Y is ##STR35## (trans); R₂ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆alkynyl, phenyl, tolyl, α-naphthyl or β-naphthyl; R₅ is hydrogen, C₁ -C₆alkyl, or benzyl; n₁ and n₂, whether the same or different, are zero oran integer between 1 and 6; R₃ and R₄, whether the same or different,may be hydrogen C₁ -C₆ alkyl or fluorine, or may form a ##STR36## groupwith a carbon atom to which they are bound; X is --(CH₂)_(m), where m iszero or 1; R₆ is hydrogen or C₁ -C₄ alkyl; and a pharmaceutically orveterinarily acceptable salt thereof.
 3. A 15-epi compound of theformula (I) ##STR37## wherein R is --COOR' wherein R₁ is hydrogen;p iszero or an integer between 1 and 7; q is 1; R₁ is hydroxy; Y is--CH═CH-- (trans); R₂ is hydrogen or C₁ -C₆ alkyl; R₅ is hydrogen or C₁-C₆ alkyl; n₁ and n₂, whether the same or different, are zero or aninteger between 1 and 6; R₃ and R₄, whether the same or different, arehydrogen, C₁ -C₆ alkyl or fluorine; X is --(CH₂)_(m) wherein m is zeroor 1; R₆ is hydrogen or C₁ -C₄ alkyl; and a pharmaceutically orveterinarily acceptable salt thereof.
 4. A 15-epi compound of theformula (I) ##STR38## wherein R is --COOR' wherein R' is hydrogen or C₁-C₆ alkyl;p is zero or an integer between 1 and 7; q is 1; R₁ ishydroxy, C₁ -C₆ alkoxy, benzyloxy, alkanoyloxy, or benzoyloxy; Y ischosen from the group --CH₂ CH₂ --, --CH═CZ₁ (cis) and --CH═CZ₁ (trans)where Z₁ is hydrogen or halogen; R₂ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, phenyl, tolyl, α-naphthyl or β-naphthyl; R₅ ishydrogen, C₁ -C₆ alkyl, or benzyl; n₁ and n₂, whether the same ordifferent, are zero or an integer between 1 and 6; R₃ and R₄, whetherthe same or different, may be hydrogen, C₁ -C₆ akyl or may form a##STR39## group with a carbon atom to which it is bound; X is chosenfrom O and S; R₆ is phenyl, tolyl, α-naphthyl or β-naphthyl, optionallysubstituted with one or more halogen, C₁ -C₆ alkyl or C₁ -C₆ alkoxy; anda pharmaceutically or veterinarily acceptable salt thereof, with theproviso that when X is O and R₂ is hydrogen, C₁ -C₆ alkyl or C₂ -C₆alkenyl, R₆ is α-naphthyl or β-naphthyl, optionally substituted with oneor more halogen, C₁ -C₆ alkyl, halo-C₁ -C₆ -alkyl or C₁ -C₆ alkoxy.
 5. Acompound of formula (I) ##STR40## wherein R is --COOR' wherein R' ishydrogen or C₁ -C₆ alkyl;p is zero or an integer between 1 and 7; q is1; R₁ is hydrogen, C₁ -C₆ alkoxy, benzoyloxy, alkanoyloxy or benzoyloxy;Y is chosen from the group: --CH₂ --CH₂, ##STR41## (cis); ##STR42##(trans) where Z₁ is hydrogen or halogen; R₂ is C₂ -C₆ alkynyl, phenyl,tolyl, α-naphthyl or β-naphthyl; R₅ is hydrogen, C₁ -C₆ alkyl, benzyl;n₁ and n₂, whether the same or different, are zero or an integer between1 and 6; R₃ and R₄, whether the same or different, may be hydrogen, C₁-C₆ alkyl or may form a ##STR43## group with a carbon atom to which theyare bound; X is chosen from --O--, and --S--; R₆ is a substituent chosenfrom (a') C₁ -C₄ alkyl, or (b') a C₃ -C₉ cycloalkyl, C₃ -C₉cycloalkenyl, norbornyl or adamantyl radical, optionally substitutedwith one or more C₁ -C₆ alkyl and C₁ -C₆ alkoxy groups; and apharmaceutically or veterinarily acceptable salt thereof.
 6. Compound ofclaim 2 wherein p is an integer between 1 and 5; R₂ is hydrogen or C₁-C₆ alkyl; R₅ is hydrogen or C₁ -C₆ alkyl; R₃ and R₄ are independentlyhydrogen, methyl or fluorine; n₁ is zero or 1; and n₂ is zero or aninteger of 1 to
 3. 7. A compound selected from the group consistingof:d,l:15-epi-PGI₂ ; nat-15-epi-PGI₂ ; ent-15-epi-PGI₂ ;nat-11,15-diepi-PGI₂ ; ent-11,15-diepi-PGI₂ ; and the compounds listedbelow in the d,l forms and as individual nat- and enantio-isomers:15-epi-20-methyl-PGI₂ ; 15-epi-16S,20-dimethyl-PGI₂ ;15-epi-16R,20-dimethyl-PGI₂ ; 15epi-20-ethyl-PGI₂ ;15-epi-16S-methyl-PGI₂ ; 15-epi-16R-methyl-PGI₂ ;15-epi-16,16-dimethyl-PGI₂ ; 15-epi-16(S),(R) or (S,R)-fluoro-PGI₂ ;andthe corresponding 11,15-diepi derivatives, and the corresponding methylesters, as well as the pharmaceutical or veterinary acceptable salts ofthe acids listed above.
 8. 15-epi-PGI₂ in the d,l, nat- and enantio-form, and a pharmaceutically or veterinarily acceptable salt thereof. 9.15-epi-20-methyl-PGI₂ in the d,l, nat- and enantio- form, thecorresponding methyl ester, and a pharmceutically or veterinarilyacceptable salt of the acid.
 10. A thrombi and clot dissolvingcomposition containing a thrombi and clot dissolving amount of acompound of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, and a pharmaceuticallyacceptable carrier or diluent.
 11. A platetlet aggregation inhibitingcomposition containing a platelet aggregation inhibiting amount of acompound of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 and a pharmaceuticallyacceptable carrier or diluent.
 12. Method of inhibiting plateletaggregation in a patient in need of such inhibition, such methodcomprising adminstering to said patient a therapeutically effectiveamount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8 or
 9. 13. Method ofclaim 12, wherein said amount is an amount of about 0.005 to about 20mg./kg./day.
 14. Method if dissolving previously formed thrombi andclots in a mammal, said method comprising adminstering to said mammal atherapeutically effective amount of a compound of claim 1, 2, 3, 4, 5,6, 7, 8 or
 9. 15. Method of claim 14, wherein said amount is an amountof about 0.005 to about 20 mg./kg./day.